title: Opening or closing the lock? When reactivity is the key to biological activity.
abstract: Thiol-mediated processes play a key role to induce or inhibit inflammation proteins. Tailoring the reactivity of electrophiles can enhance the selectivity to address only certain surface cysteines. Fourteen 2',3,4,4'-tetramethoxychalcones with different α-X substituents (X=H, F, Cl, Br, I, CN, Me, p-NO2-C6H4, Ph, p-OMe-C6H4, NO2, CF3, COOEt, COOH) were synthesized, containing the potentially electrophilic α,β-unsaturated carbonyl unit. The assessment of their reactivity as electrophiles in thia-Michael additions with cysteamine shows a change in the reactivity of more than six orders of magnitude. Moreover, a clear correlation between their reactivity and an influence on the inflammation proteins heme oxygenase-1 (HO-1) and the inducible NO synthase (iNOS) is demonstrated. As the biologically most active compound, the α-CF3 -chalcone is shown to inhibit the NO production in RAW264.7 mouse macrophages in the nanomolar range.
authors.affiliation: Institute of Organic Chemistry, University of Regensburg, Universitätsstraße 31, 93053 Regensburg (Germany).
authors.forename: Nafisah
authors.initials: N
authors.lastname: Al-Rifai
authors.forename: Hannelore
authors.initials: H
authors.lastname: Rücker
authors.forename: Sabine
authors.initials: S
authors.lastname: Amslinger
mesh_terms: D000818:Animals; D002599:Chalcone / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D013438:Sulfhydryl Compounds; D002599:Chalcone
keywords: chalcones; electrophiles; inflammation proteins; reactivity tuning; thiols